Pantoprazole is a gastric acid secretion inhibitor. The systematic chemical name of pantoprazole is 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole and its molecular structure is represented by formula (I).

U.S. Pat. No. 4,758,579 discloses that pantoprazole and many other fluoroalkoxy substituted benzimidazoles are gastric acid secretion inhibitors. The '579 patent states that pantoprazole can be prepared by oxidation of the sulfide analog with meta-chloroperbenzoic acid by following a procedure described in Example 2 of the '579 patent. According to Example 2, the oxidation is conducted in dichloromethane. The reaction mixture is quenched with sodium thiosulfate and sodium carbonate. The product is extracted from the aqueous phases with dichloromethane, washed with sodium thiosulfate, dried over magnesium sulfate and concentrated. The residue is then crystallized from diisopropyl ether and recrystallized from a mixture of dichloromethane and diisopropyl ether. Although pantoprazole sodium is the subject of a claim in the '579 patent, a detailed procedure for converting pantoprazole to its sodium salt is not set forth in the '579 patent.
Kohl, B. et al. J. Med. Chem. 1992, 35, 1049-57 reports a study of the inhibitor activity and pH dependent stability of a series of dimethoxypyridyl-substituted methylsulfinylbenzimidazoles, including pantoprazole. Pantoprazole sodium sesquihydrate was prepared by adding 6 N NaOH to a solution of pantoprazole in a 6:1 ethanol:dichloromethane mixture at 20° C. After 10 minutes, diisopropyl ether was added until the mixture became turbid. After stirring for another two hours, the precipitate was collected by filtration, washed with isopropyl ether and dried under vacuum at 40° C. The results of C, H, N and S analysis, coupled with the anticipated structure and molecular formula of pantoprazole indicated that the product contained 6.5% water, corresponding to a sesquihydrate (1.5 mol./mol.) level of hydration.
International Publication No. WO 91/19710 discloses a monohydrate form of pantoprazole sodium. The monohydrate form obtained by following the teachings of the '710 publication crystallizes as small cubic crystals, has a melting point of 150-153° C. and dissolves with difficulty in acetone. According to the '710 publication, the sesquihydrate contains 6.0-6.5% water and has a melting point of 137-140° C. The pantoprazole sodium monohydrate of the '710 publication can be made by dissolving pantoprazole in acetone or another low ketone and adding sodium hydroxide solution to the mixture. The monohydrate is obtained immediately in pure form after adding the sodium hydroxide solution. Alternatively, the monohydrate of the '710 publication can be obtained by crystallization from a solution prepared by dissolving pantoprazole sodium sesquihydrate in acetone or other lower ketone.
Pantoprazole is the active ingredient of a pharmaceutical product that is marketed in the United States by Wyeth-Ayerst Inc. under the brand name Protonix®. Protonix® is approved by the U.S. Food and Drug Administration for short term treatment of erosive esophagitis associated with gastroesophageal reflux disease (“GERD”), maintenance of healing of erosive esophagitis and pathological hypersecretory conditions including Zollinger-Ellison syndrome. According to the package insert for Protonix®, the product contains a monosodium salt of pantoprazole (hereafter “pantoprazole sodium”) in a sesquihydrate state of hydration.
The present invention relates to the solid state physical properties of pantoprazole sodium. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography (“PXRD”), solid state 13C NMR spectrometry and infrared spectrometry.
These spectroscopic and utilitarian properties can be influenced by controlling the conditions under which a compound is obtained in solid form. There is a wide variety of techniques that have the potential of producing different crystalline forms of a compound. Examples include crystallization, crystal digestion, sublimation and thermal treatment. However, none of these techniques can be expected a priori to produce a new solid state form of a compound.
The present invention also relates to solvates of pantoprazole sodium. When a substance crystallizes out of solution, it may trap molecules of solvent at regular intervals in the crystal lattice. Solvation also affects utilitarian physical properties of the solid state like flowability and dissolution rate.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. New polymorphic forms and solvates of pantoprazole have now been discovered.